Abstract
Introduction:
The use of corticosteroid injections for short-term pain relief for knee osteoarthritis can have deleterious adverse effects. Amniotic tissue has shown promise in vitro; therefore, this study compared a morcellized injectable amniotic tissue allograft to corticosteroid injection.
Methods:
Eighty-one patients with symptomatic severe knee osteoarthritis (Kellgren-Lawrence grade 3 to 4) were prospectively randomized to either a double-blinded single injection of BioDRestore (Integra LifeSciences; n = 39) or triamcinolone acetonide (n = 42). Knee Injury and Osteoarthritis Outcome Score (KOOS), Single Alpha Numeric Evaluation, visual analog scale (VAS) pain, Lysholm Rating, and Veterans-Rand-12 scales at baseline, 6 weeks, 3, 6, and 12 months were analyzed.
Results:
No differences were observed in adverse reactions or patient reported outcomes (PROs); however, a notable continued improvement was found in the amnion group from 6 weeks to 1 year for Single Alpha Numeric Evaluation, Lysholm, and KOOS Symptoms, Pain, activities of daily living [ADL], QofL. The minimal clinically important difference (MCID) was met for Lysholm, KOOS ADL, and KOOS pain.
Discussion:
Both amnion and steroid injections showed an initial improvement in pain relief and function at 6 weeks; however, more patients in the amniotic tissue group maintained pain relief and function at the 1-year follow-up. The mixed results suggest that amniotic tissue injections may be a safe and effective alternative to corticosteroid injections.
Osteoarthritis (OA) of the knee is one of the most common causes of musculoskeletal pain and can lead to notable pain and functional decline.1 When symptoms cannot be controlled by conservative measures, such as oral medications, bracing treatment, and exercise, the current mainstay of treatment involves the use of intra-articular injections. Corticosteroid injections often become an important treatment for providing symptomatic relief for patients with knee arthritis not yet severe enough for knee arthroplasty.
The effectiveness of the corticosteroid is often short term (1 week to 3 months).2 There are also potential deleterious concerns of intra-articular corticosteroid injections, especially when administered repeatedly.3 Corticosteroid injections transiently increase blood glucose levels, which may be concerning in patients with diabetes mellitus.4 These drawbacks have led to the alternative use of intra-articular hyaluronic acid (HA) injections for knee OA. However, despite some reports showing reasonable clinical experience, HA injections have not demonstrated superiority to corticosteroid injections with minimum clinically important differences. As a result, the American Academy of Orthopaedic Surgeons has recently recommended against the use of HA in their clinical practice guidelines.5
Biologic injections have also been suggested as an alternative treatment, especially when knee arthroplasty is contraindicated, as with patients who are young, wishing to maintain very high activity levels, not yet end stage, or have notable medical comorbidities. The term “biologic” remains poorly defined but may include platelet-rich plasma injections, bone marrow aspirate concentrate, adipose-derived stromal vascular fraction, and allogeneic amniotic products.
Amniotic tissue has been investigated for various medical applications, such as diabetic foot and corneal ulcers, due to its ability to support soft-tissue repair, reduce inflammation, and minimize scar tissue formation.6,7 Amnion contains anabolic growth factors, including transforming growth factor-α, transforming growth factor-beta, basic fibroblast growth factor, epidermal growth factor, and platelet-derived growth factor. It also contains tissue inhibitors of metalloproteinases (tissue inhibitors of metalloproteinases [TIMP]-1, TIMP-2, and TIMP-4), along with proteins that upregulate anti-inflammatory pathways, such as interleukin (IL)-4, IL-10, and IL-1 receptor antagonist-1.8,9 Amniotic membrane has free HA and high-density core proteins bonded to HA. The combined effect of these properties makes it chondroprotective, naturally anti-inflammatory, and may improve synovial joint homeostatis.10
Despite the theoretic advantages of amniotic membrane injections for knee OA, its clinical efficacy compared with standard treatments is unknown. The purpose of the study was to compare corticosteroid injection to a morcellized, flowable tissue allograft derived from amniotic tissues in patients with notable knee OA. Our hypothesis was an improved and more sustained patient-reported function, pain, and quality of life outcomes that would be found in the amnion group than in the corticosteroid group.
Methods
Trial Design
The study was a randomized, parallel, controlled trial. Approval was obtained from the Prisma Health-Upstate Institutional Review Board before initiation. The study was registered on clinicaltrials.gov (NCT02767492). Funding was provided by Integra LifeSciences. No author had a conflict of interest relating to the industry, and all data were kept blinded to the industry partner throughout its completion. The industry partner had also no role in data interpretation or manuscript preparation.
Participants
Ninety patients with symptomatic advanced knee OA were enrolled in the study between 2017 and 2018. Inclusion criteria included adults between the ages of 18 and 80 years, Kellgren-Lawrence (KL) grade 3 to 4 OA, willingness to undergo a knee injection, and a body mass index of <40. The KL grade was determined by the treating physician using standing radiograph. Exclusion criteria included patients with ligamentous instability, diabetes mellitus (type I or II), inflammatory arthropathy, fibromyalgia, chronic fatigue syndrome, pregnant or nursing females, or chronic narcotics use. Patients were also excluded if the study knee had an intra-articular injection within the previous 3 months, arthroscopic surgery within the previous year, or history of knee arthroplasty.
Interventions
Patients were prospectively randomized using a computer-generated program. Patients either received a single injection of 2 mL of 40 mg/mL triamcinolone acetonide with 3 mL of saline or 2 mL of morcellized amniotic membrane in suspension (BioDRestore; Integra LifeSciences) with 3 mL of saline. Randomization allocation was 1:1 between the two treatment groups.
The injected quantity was identical, and syringes were covered with opaque tape to obscure the appearance of the medication. Injections were done by fellowship-trained orthopaedic knee surgeons in a high-volume, tertiary orthopaedic practice using their preferred arthrocentesis technique. They were blinded during initial injection and throughout the study period. If patients had a noticeable effusion at the time of the injection, a concomitant aspiration was allowed before the injection.
Medications that could affect outcomes were controlled during the first 6 months of the investigation. Prohibited medications included oral steroids, steroid injections, and viscosupplementation injections. Medications approved for use included acetaminophen and ibuprofen.
Outcomes
The primary outcome measures were the Knee Injury and Osteoarthritis Outcome Score (KOOS), Single Alpha Numeric Evaluation (SANE), visual analog scale (VAS), pain scale, Lysholm Rating Scale, and Veterans-Rand-12 (VR-12) at 6 weeks and 3, 6, and 12 months postinjection.
Sample Size Estimate
An a priori power analysis was done to determine necessary sample sizes for the primary outcome measures of VAS, VR-12, KOOS, Lysholm, and SANE scales at baseline and each follow-up period. A sample size estimation was constructed using a repeated-measures analysis of covariance (RM-ANCOVA) assuming normal distributions among the two independent groups, five time points for two groups and five outcome measures, and assuming an effect size of 0.20 (small). Measuring global effects, with an expected 80% power and a standard error of probability of 0.05, the need for a minimum sample size of 70 for statistical significance (35 per group) was determined. A sample size of 84 subjects was selected to allow for a 20% attrition rate. An intention to treat and a chains equation was employed, along with a multiple imputation method in which predictor could be assigned.
Statistical Methods
Appropriate tests of differences (eg, Student t tests and chi square analyses) were used to compare baseline differences in descriptive statistics (ie, pain, range of motion) between the two groups. Any adverse event was recorded and compared between groups. A RM-ANCOVA was used to measure differences between the targeted outcome measures (Pain, VR12 physical component score [PCS] and mental component score [MCS], Lysholm, and KOOS measures) at each of the given time points (baseline, 6 weeks, and 3, 6, and 12 months). A RM-ANCOVA was used to compare means across variables based on repeated observations while controlling for potential confounding variables. In our study, we controlled for baseline scores of each outcome variable. Partial eta-squared effect size measures were captured to demonstrate magnitude of effect. Suggested norms for partial eta-squared include small = 0.01; medium = 0.06; large = 0.14.
In addition, we compared the proportions of patients who improved versus worsened using the same outcomes and the mean change scores from 6 weeks to 1 year between groups using a chi square analysis. For all analyses, a P value of <0.05 was considered statistically significant.
Results
Ninety patients with symptomatic advanced knee OA were enrolled in the study. Eighty-one patients met eligibility criteria and were randomized. Overall, 39 patients in the amnion group and 42 patients in the corticosteroid group were enrolled. No adverse events or injection adverse effects occurred in either study group. Baseline characteristics were similar between the groups with no statistically significant differences except VAS pain (Table 1). In all comparisons, effect size magnitudes were trivial to small.
Table 1.
Baseline Comparisons Between BioDRestore and Steroid Recipients (N = 81)
| BioD Mean (SD)/Frequency N = 39 |
Steroid Mean (SD)/Frequency N = 42 |
P | |
| Age | 61.82 (8.12) | 63.45 (8.87) | 0.39 |
| Sex | 15 = male 24 = female |
16 = male 26 = female |
0.97 |
| Race | 36 = white 2 = black 1 = unknown |
38 = white 3 = black 1 = unknown |
0.93 |
| Ethnicity | 37 = Non-Hispanic 0 = Hispanic 2 = Unknown |
41 = Non-Hispanic 1 = Hispanic 0 = Unknown |
0.21 |
| Lysholm score | 60.15 (17.16) | 54.00 (18.67) | 0.13 |
| Kellgren Lawrence grade | 19 = 3 20 = 4 |
24 = 3 18 = 4 |
0.45 |
| Pain (VAS) | 3.51 (2.17) | 4.78 (2.36) | 0.01 |
| VR12 PCS | 35.20 (8.46) | 34.64 (7.83) | 0.75 |
| VR12 MCS | 54.87 (9.76) | 54.59 (10.93) | 0.87 |
| SANE | 54.62 (18.67) | 49.71 (20.03) | 0.27 |
| KOOS symptoms score | 59.61 (20.94) | 52.21 (19.79) | 0.11 |
| KOOS pain score | 56.27 (18.21) | 49.34 (18.95) | 0.10 |
| KOOS ADL score | 64.06 (18.37) | 56.76 (21.01) | 0.10 |
| KOOS sport/recreation score | 32.44 (22.74) | 29.64 (21.54) | 0.57 |
| KOOS QOL score | 32.37 (21.11) | 36.31 (20.90) | 0.40 |
Bold denote significance was set at P < 0.05. ADL = activities of daily living, KOOS = Knee Injury and Osteoarthritis Outcome Score, MCS = mental component score, PCS = Physical Component Score, QOL = quality of life, SANE = Single Alpha Numeric Evaluation, VAS = visual analog scale, VR12 = Veterans-Rand-12
The RM-ANCOVA revealed no statistically significant differences between the groups across time points (Table 2). Despite no statistical significance in the primary outcome measure, a dissimilar treatment response was observed. The treatment effect of steroid injection tended to decline overtime, whereas the response from the amnion injection were more sustained and continued to improve in some outcome measures (Figures 1–8). These differences were not statistically significant.
Table 2.
Comparison of Patient-Reported Outcomes for BioDRestore Versus Steroid
| 6 wk Mean (SD)/Frequency N = 81 |
3 mo Mean (SD)/Frequency N = 81 |
6 mo Mean (SD)/Frequency N = 81 |
1 Year Mean (SD)/Frequency N = 81 |
P | Effect Size | |
| Pain (VAS) | ||||||
| BioD | 3.03 (2.19) | 2.33 (1.88) | 3.13 (2.62) | 2.54 (2.28) | 0.53 | 0.00 |
| Steroid | 2.64 (2.37) | 3.52 (2.83) | 2.59 (2.58) | 2.89 (2.44) | ||
| VR12 PCS | ||||||
| BioD | 41.14 (9.89) | 42.09 (9.74) | 40.29 (10.92) | 41.04 (11.19) | 0.19 | 0.02 |
| Steroid | 40.76 (9.64) | 38.44 (11.16) | 37.55 (9.17) | 37.07 (9.01) | ||
| VR12 MCS | ||||||
| BioD | 57.03 (8.08) | 56.39 (9.56) | 56.75 (8.89) | 57.26 (9.35) | 0.70 | 0.00 |
| Steroid | 56.98 (7.84) | 55.55 (10.21) | 56.19 (10.19) | 58.33 (6.86) | ||
| Lysholm | ||||||
| BioD | 68.84 (18.35) | 71.62 (19.14) | 69.00 (19.22) | 74.82 (16.83) | 0.73 | 0.00 |
| Steroid | 72.38 (19.64) | 64.88 (21.68) | 61.02 (21.78) | 62.90 (20.13) | ||
| KOOS symptoms score | ||||||
| BioD | 66.02 (20.27) | 68.41 (20.68) | 68.04 (20.33) | 69.41 (21.14) | 0.49 | 0.01 |
| Steroid | 70.15 (18.07) | 64.20 (21.16) | 59.94 (19.49) | 63.69 (20.92) | ||
| KOOS pain score | ||||||
| BioD | 67.45 (17.64) | 70.37 (19.36) | 67.73 (20.47) | 71.15 (19.84) | 0.70 | 0.00 |
| Steroid | 70.43 (21.22) | 63.03 (23.85) | 62.89 (19.65) | 62.89 (21.24) | ||
| KOOS ADL score | ||||||
| BioD | 75.41 (17.15) | 77.71 (17.96) | 73.83 (19.46) | 77.60 (15.98) | 0.64 | 0.00 |
| Steroid | 76.22 (19.11) | 69.43 (22.15) | 67.29 (20.29) | 67.87 (20.29) | ||
| KOOS sport/recreation score | ||||||
| BioD | 47.69 (26.37) | 51.15 (30.01) | 48.33 (28.84) | 47.69 (27.57) | 0.93 | 0.00 |
| Steroid | 50.41 (26.66) | 47.85 (31.27) | 42.73 (25.33) | 39.28 (24.25) | ||
| KOOS QOL score | ||||||
| BioD | 42.46 (21.22) | 50.32 (21.50) | 48.71 (23.17) | 52.24 (25.39) | 0.47 | 0.01 |
| Steroid | 52.97 (22.13) | 48.51 (22.12) | 44.64 (21.19) | 47.76 (25.96) |
ADL = activities of daily living, KOOS = Knee Injury and Osteoarthritis Outcome Score, MCS = mental component score, PCS = Physical Component Score, QOL = quality of life, SANE = Single Alpha Numeric Evaluation, VAS = visual analog scale, VR12 = Veterans-Rand-12
Control includes baseline findings. Analyses include Repeated Measures Analysis of Covariance (RM-ANCOVA) N = 81 completers. Reported as estimated marginal means (adjusted values).
Figure 1.
Graph showing a comparison of VAS Pain scores between amnion and corticosteroid groups from baseline to final follow-up at 1 year.
Figure 8.
Graph showing a comparison of KOOS Sport/recreation scores between amnion and corticosteroid groups from baseline to final follow-up at 1 year. KOOS = Knee Injury and Osteoarthritis Outcome Score.
Both groups had notable within-group improvements in VAS and PROs at 6 weeks postinjection (Table 3, Figure 1). When comparing PROs from the 6-week to the 1-year follow-up, the percentage of patients who continued to improve was markedly higher in the amnion group compared with the corticosteroid group with KOOS Symptoms (Figure 2), KOOS ADL (Figure 3), KOOS QoL (Figure 4), SANE (Figure 5), and Lysholm (Figure 6, Table 4). Lysholm, KOOS ADL, and KOOS pain also met MCID. The proportion of patients who improved on the global health assessments (VR-12, Figure 7), and sports-related outcome scores (KOOS Sport/Recreation, Figure 8) from 6 weeks to 1 year were not different between the groups (Table 4).
Table 3.
Comparison of Proportions of Patients Who Improved and Mean Change Scores From 6 Weeks to 1 Year Between BioDRestore and Steroid
| BioD, Number (%) | Mean Change Score | Steroid, Number (%) | Mean Change Score | P | |
| KOOS symptoms score | |||||
| Improved | 23 (66%) | 13.4 | 13 (38%) | 10.2 | 0.02 |
| Worsened | 12 (34%) | −13.9 | 21 (62%) | −20.6 | |
| KOOS pain score | |||||
| Improved | 21 (60%) | 14.0 | 10 (29%) | 12.5 | 0.01 |
| Worsened | 14 (40%) | −13.6 | 24 (71%) | −19.1 | |
| KOOS ADL score | |||||
| Improved | 20 (57%) | 11.8 | 8 (24%) | 5.5 | <0.01 |
| Worsened | 15 (43%) | −11.9 | 26 (76%) | −15.9 | |
| KOOS sport/recreation score | |||||
| Improved | 17 (48%) | 15.3 | 13 (38%) | 10.4 | 0.39 |
| Worsened | 18 (52%) | −17.2 | 21 (62%) | −26.7 | |
| KOOS QOL score | |||||
| Improved | 28 (80%) | 14.5 | 12 (35%) | 15.6 | <0.01 |
| Worsened | 7 (20%) | −16.9 | 22 (65%) | −20.4 | |
| VAS pain intensity | |||||
| Improved | 21 (60%) | 1.9 | 20 (59%) | 0.8 | 0.92 |
| Worsened | 14 (40%) | −2.1 | 14 (41%) | −2.9 | |
| SANE | |||||
| Improved | 25 (71%) | 13.3 | 11 (32%) | 8.3 | <0.01 |
| Worsened | 10 (29%) | −11.2 | 23 (68%) | −19.6 | |
| Lysholm | |||||
| Improved | 24 (71%) | 5.9 | 8 (24%) | 4.0 | <0.01 |
| Worsened | 10 (29%) | −7.8 | 25 (76%) | −9.9 | |
| VR-12 PCS | |||||
| Improved | 18 (51%) | 4.3 | 12 (35%) | 5.5 | 0.18 |
| Worsened | 17 (49%) | −6.3 | 22 (65%) | −4.5 | |
| VR-12 MCS | |||||
| Improved | 20 (57%) | 14.9 | 17 (50%) | 12.7 | 0.55 |
| Worsened | 15 (42%) | −32.8 | 17 (50%) | −21.9 |
Bold denotes significance was set at P < 0.05. ADL = activities of daily living, KOOS = Knee Injury and Osteoarthritis Outcome Score, PCS = Physical Component Score, QOL = quality of life, SANE = Single Alpha Numeric Evaluation, VAS = visual analog scale, VR12 = Veterans-Rand-12
Codes as improved or worsened from 6 weeks to 1 year.
Figure 2.
Graph showing a comparison of KOOS Symptoms scores between amnion and corticosteroid groups from baseline to final follow-up at 1 year. KOOS = Knee Injury and Osteoarthritis Outcome Score.
Figure 3.
Graph showing a comparison of KOOS ADL scores between amnion and corticosteroid groups from baseline to final follow-up at 1 year. ADL = activities of daily living, KOOS = Knee Injury and Osteoarthritis Outcome Score.
Figure 4.
Graph showing a comparison of KOOS QOL scores between amnion and corticosteroid groups from baseline to final follow-up at 1 year. KOOS = Knee Injury and Osteoarthritis Outcome Score, QOL = quality of life.
Figure 5.
Graph showing a comparison of SANE scores between amnion and corticosteroid groups from baseline to final follow-up at 1 year. SANE = Single Alpha Numeric Evaluation.
Figure 6.
Graph showing a comparison of Lysholm scores between amnion and corticosteroid groups from baseline to final follow-up at 1 year.
Table 4.
Differences in Laboratory Values at 6 Months Between BioDRestore and Steroid
| Laboratory Variable | N | BioD, Mean (SD) |
Steroid Comparative Group, Mean (SD) |
P |
| IL-1 beta concentration (pg/mL) | 32 | 1.67 (3.82) | 1.61 (2.68) | 0.43 |
| IL-8 concentration detected (pg/mL) | 23 | 50.32 (126.51) | 16.32 (31.41) | 0.19 |
| IL-1RA concentration (pg/mL) | 25 | 513.34 (437.79) | 293.07 (247.99) | 0.25 |
| IL-6 concentration (pg/mL) | 20 | 23.83 (27.97) | 11.78 (16.34) | 0.38 |
| PGE2 concentration detected (pg/mL) | 27 | 452.89 (338.80) | 502.96 (484.38) | 1.00 |
| TNF-α concentration detected (pg/mL) | 22 | 0.51 (0.21) | 0.44 (0.21) | 0.67 |
IL = interleukin, PGE2 = prostaglandin-E2, RA = receptor antagonist, TNF = transforming growth factor
All analyses calculated using a Mann-Whitney U test.
Figure 7.
Graph showing a comparison of VR-12 Physical Component scores (PCS) between amnion and corticosteroid groups from baseline to final follow-up at 1 year. VR12 = Veterans-Rand-12.
Discussion
This double-blinded, randomized, prospective, clinical trial found no statistical difference between steroid and amniotic tissue injections when assessed by PROs or VAS summed across all time points. However, the percentage of patients who continued to improve from 6 weeks to 1 year was markedly higher in the amnion group in multiple PROs (KOOS Symptoms, KOOS Pain, KOOS ADL, KOOS QoL, SANE, Lysholm). Lysholm, KOOS ADL, and KOOS pain also met MCID. Although not statistically significant, patients in the amnion group had a more sustained response to the injection, with most of the PROs showing continued improvements compared with a gradual decline in the steroid group. Further studies may reveal patient factors associated with a more predictable response. The optimal dose for amnion is also unknown, and a higher dose could produce a more robust effect.
We attempted to determine differences in the host response between the groups by analyzing synovial fluid. Patients with a noticeable effusion at the time of the injection had a preinjection aspiration. An attempted repeat aspiration was done in the same patients at the 6-month follow-up. Synovial fluid samples were analyzed by enzyme-linked immunosorbent assay for inflammatory factors (IL-1β, IL-6 and TNF-α), anti-inflammatory factors (IL-receptor antagonist-1 and IL-10), and pain signals (prostaglandin-E2, IL-8). Not enough patients had effusions or successful aspirations for meaningful statistical analysis. However, in the samples available, no differences were found in any soluble inflammatory, anti-inflammatory, or pain factors between the groups.
Biologic injections may be an effective alternative to corticosteroid injections for treating knee OA. Amnion could provide a promising source of mesenchymal stromal cells.11 The cells obtained from the placenta are younger than those found in adult bone marrow, adipose tissue, and peripheral blood. Amnion-derived mesenchymal stromal cells have shown promising ability to differentiate into bone and cartilage.12 Other advantages of amnion-derived cells include a high proliferative capacity and low immunogenicity,13 making them well-suited for allotransplantation. There is also no donor site morbidity compared with some other biologic options. There is a preparation drawback to amnion-derived allograft products because the process can include cryopreservation, packaging, terminal sterilization, and thawing that eliminates the viable stem cells. Nevertheless, the natural cytokines, growth factors, and extracellular matrix proteins that promote healing tissue and repair remain. Worth noting is that there may be religious and political controversies related to the use of amnion as well.
In vitro studies were initially conducted to study the effect of amnion on cartilage damage. Willett et al14 used a Lewis rat medial meniscus transection model of OA to show that amnion/chorion membrane resulted in notable reduction in cartilage erosions, attenuation, and focal defects. Raines et al15 used the same rat model to show that human, cryopreserved, particulate amniotic membrane/umbilical cord reduces cartilage degeneration and improved the Osteoarthritis Research Society Internationa histological joint score.
These in vitro studies laid the groundwork for clinical studies. Vines et al conducted the first pilot study in six patients with KL grade 3 and 4 knee OA. They studied adverse events and PROs after a single, 2-mL, intra-articular knee injection of a cryopreserved human amniotic suspension.16 Each patient was followed with an immunologic panel, including white blood cell count, C-reactive protein, and erythrocyte sedimentation rate levels. No patient developed a severe adverse event. Although not powered to allow for statistical analysis, PROs improved throughout the 12-month study period. These findings show safety and a similar sustained response to amnion as was found in our patients.
Farr et al17 conducted the first, level I, multicenter, randomized, controlled trial comparing amniotic suspension allograft injections, HA, and placebo in 200 patients with knee OA. Only 13.2% of patients in the amnion group reported unacceptable pain at 3 months, compared with 68.8% in the HA group and 75% in saline group. Patients in the amnion group demonstrated markedly greater improvements in VAS, KOOS pain, and KOOS-ADL scores compared with those in the HA group at 3 months and both groups at 6 months. Although limited by short follow-up, the authors concluded that patients in the amnion group had greater improvements in PROs and fewer patients reported unacceptable pain compared with patients receiving HA or saline. Similar to our study, they found a sustained response with amnion, with patients in the amnion group having greater improvement from baseline to 6-month follow-up for several scores. Interestingly, they also found a better responder rate and a greater improvement in responder rate over time in the amnion group, which may suggest a delayed onset of action and continued improvement. Our study contrasts the one by Farr et al17 in that our control group consisted of corticosteroid injection because this is more often used in clinical practice.
Alden et al18 conducted a retrospective review of 82 patients treated for symptomatic OA with 100-mg micronized dehydrated human amnion/chorion membrane and followed for 6 months. The KOOS score improved from 40 at baseline to 52 (6 weeks), 62 (3 months), and 65 (6 months). Quality of life and sports/recreation domains improved by 111% and 118%, respectively, at 6 months. Although limited by no control group, the authors found a sustained response and improved activity levels of the patients at last follow-up.
It is challenging to understand the cost-benefit of administering more expensive injections, such as amniotic tissue. Until cost reduction measures, such as delaying the need for total knee arthroplasty, can be determined, the cost-benefit will remain elusive despite the limited positive clinical effects of these more expensive injections. Moreover, these products are currently not available for study outside of FDA-approved trials and are not being marketed or sold, making current study difficult. If further randomized controlled large human trials are permitted, the preferred dosing and targeting of these products for treating patients with knee OA can be more clearly defined.
Although others have explored amnion injections in a trial, our study is the first double-blind, randomized, prospective study for knee OA. Nonetheless, it does have limitations. We chose to use corticosteroid as the control group, as it represents the current standard of care for knee injections. However, this does not allow comparison of other medications, such as HA. Because of the differences in viscosity, it would be difficult to blind the investigators to HA treatment. In addition, because the literature has not shown consistent benefit of HA over corticosteroid injection, we consider the use of corticosteroid a sufficient control. The ideal dose of amnion is unknown. The dose selection was based on its known safety profile, and no adverse reactions were found. A subsequent dosing study may reveal a more therapeutic response with higher doses or a series of injections. An a priori power analysis determined the optimal subject number of 70 patients. We initially enrolled 90 subjects, and 81 patients met eligibility. We considered this sufficient to counteract attrition. Only 34 subjects in the steroid group and 35 patients in the amnion group completed all questionnaires. Because the primary outcome was outcomes summed over all time points, patients with incomplete data sets were not included in final analysis. The final analysis was one patient less than our intended number of subjects for optimal power. Similar attrition occurred in both groups, and we do not feel that this markedly affects the study results. Finally, a potential bias from industry support could be considered a limitation. However, the investigators had no financial involvement or conflicts, no data were shared with industry during the study period, and an independent statistician from outside the investigators' institution was used to perform all statistical analyses.
Conclusion
This double-blinded, prospective, randomized, controlled trial found no overall difference in function or pain relief between corticosteroid and amnion injections for patients with knee OA. Both amnion and steroid injections showed similar improvement in pain relief and function at 6 weeks follow-up. Beyond 6 weeks, a higher percentage of subjects in the amnion group maintained pain relief and function compared with the corticosteroid group. Although not statistically significant, the general trend of amnion injections demonstrated continued improvement rather than the general decline seen in the corticosteroid group. Further study regarding optimal dosing of amnion may reveal its true efficacy.
Footnotes
Funding was provided by Integra LifeSciences, Princeton, NJ.
None of the following authors or any immediate family member has received anything of value from or has stock or stock options held in a commercial company or institution related directly or indirectly to the subject of this article: Dr. Pill, Dr. Ahearn, Dr. Tokish, Dr. Cook, Dr. Siffri, Dr. Mercuri, Dr. Burnikel, Dr. Cassas, Dr. Wyland, Mr. Sawvell, Mr. Wright, Dr. Hutchinson, Dr. Bynarowicz, Dr. Adams, and Dr. Kissenberth.
Institution where work was done: Steadman Hawkins Clinic of the Carolinas, Prisma Health-Upstate, Greenville, SC.
Contributor Information
Briggs Ahearn, Email: briggsahearn@gmail.com.
John M. Tokish, Email: jtoke95@aol.com.
Chad Cook, Email: chad.cook@duke.edu.
Paul J. Siffri, Email: Paul.Siffri@prismahealth.org.
Jeremy J. Mercuri, Email: JMERCUR@clemson.edu.
Brian Burnikel, Email: Brian.Burnikel@prismahealth.org.
Kyle J. Cassas, Email: Kyle.Cassas@prismahealth.org.
Douglas J. Wyland, Email: douglas.wyland@prismahealth.org.
Emily Sawvell, Email: esawvel@clemson.edu.
Noah Wright, Email: npwrigh@clemson.edu.
Josh Hutchinson, Email: jhutch34@uthsc.edu.
Taylor Bynarowicz, Email: taylor.m.hall16@gmail.com.
Kyle J. Adams, Email: kyle.adams@prismahealth.org.
Michael J. Kissenberth, Email: mike.kissenberth@hawkinsfoundation.com.
References
- 1.Dawson J, Linsell L, Zondervan K, et al. : Epidemiology of hip and knee pain and its impact on overall health status in older adults. Rheumatology (Oxford) 2004;43:497-504. [DOI] [PubMed] [Google Scholar]
- 2.Levy DM, Petersen KA, Scalley Vaught M, Christian DR, Cole BJ: Injections for knee osteoarthritis: Corticosteroids, viscosupplementation, platelet-rich plasma, and autologous stem cells. Arthroscopy 2018;34:1730-1743. [DOI] [PubMed] [Google Scholar]
- 3.McAlindon TE, LaValley MP, Harvey WF, et al. : Effect of intra-articular triamcinolone vs saline on knee cartilage volume and pain in patients with knee osteoarthritis: A randomized clinical trial. JAMA 2017;317:1967-1975. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Moon HJ, Choi KH, Lee SI, Lee OJ, Shin JW, Kim TW: Changes in blood glucose and cortisol levels after epidural or shoulder intra-articular glucocorticoid injections in diabetic or nondiabetic patients. Am J Phys Med Rehabil 2014;93:372-378. [DOI] [PubMed] [Google Scholar]
- 5.Jevsevar DS: Treatment of osteoarthritis of the knee: Evidence-based guideline, 2nd edition. J Am Acad Orthop Surg 2013;21:571-576. [DOI] [PubMed] [Google Scholar]
- 6.Gruss JS, Jirsch DW: Human amniotic membrane: A versatile wound dressing. Can Med Assoc J 1978;118:1237-1246. [PMC free article] [PubMed] [Google Scholar]
- 7.Niknejad H, Peirovi H, Jorjani M, Ahmadiani A, Ghanavi J, Seifalian AM: Properties of the amniotic membrane for potential use in tissue engineering. Eur Cell Mater 2008;15:88-99. [DOI] [PubMed] [Google Scholar]
- 8.McQuilling JP, Vines JB, Kimmerling KA, Mowry KC: Proteomic comparison of amnion and chorion and evaluation of the effects of processing on placental membranes. Wounds 2017;29:E36-E40. [PMC free article] [PubMed] [Google Scholar]
- 9.Goldring MB: Osteoarthritis and cartilage: The role of cytokines. Curr Rheumatol Rep 2000;2:459-465. [DOI] [PubMed] [Google Scholar]
- 10.Mori Y, Saito T, Chang SH, et al. : Identification of fibroblast growth factor-18 as a molecule to protect adult articular cartilage by gene expression profiling. J Biol Chem 2014;289:10192-10200. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Marmotti A, Peretti GM, Mattia S, et al. : A future in our past: The umbilical cord for orthopaedic tissue engineering. Joints 2014;2:20-25. [PMC free article] [PubMed] [Google Scholar]
- 12.Topoluk N, Hawkins R, Tokish J, Mercuri J: Amniotic mesenchymal stromal cells exhibit preferential osteogenic and chondrogenic differentiation and enhanced matrix production compared with adipose mesenchymal stromal cells. Am J Sports Med 2017;45:2637-2646. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Lange-Consiglio A, Tassan S, Corradetti B, et al. : Investigating the efficacy of amnion-derived compared with bone marrow-derived mesenchymal stromal cells in equine tendon and ligament injuries. Cytotherapy 2013;15:1011-1020. [DOI] [PubMed] [Google Scholar]
- 14.Willett NJ, Thote T, Lin AS, et al. : Intra-articular injection of micronized dehydrated human amnion/chorion membrane attenuates osteoarthritis development. Arthritis Res Ther 2014;16:R47. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Raines AL, Shih MS, Chua L, Su CW, Tseng SC, O'Connell J: Efficacy of particulate amniotic membrane and umbilical cord tissues in attenuating cartilage destruction in an osteoarthritis model. Tissue Eng A 2017;23:12-19. [DOI] [PubMed] [Google Scholar]
- 16.Vines JB, Aliprantis AO, Gomoll AH, Farr J: Cryopreserved amniotic suspension for the treatment of knee osteoarthritis. J Knee Surg 2016;29:443-450. [DOI] [PubMed] [Google Scholar]
- 17.Farr J, Gomoll AH, Yanke AB, Strauss EJ, Mowry KC, ASA Study Group: A randomized controlled single-blind study demonstrating superiority of amniotic suspension allograft injection over hyaluronic acid and saline control for modification of knee osteoarthritis symptoms. J Knee Surg 2019;32:1143-1154. [DOI] [PubMed] [Google Scholar]
- 18.Alden KJ, Harris S, Hubbs B, Kot K, Istwan NB, Mason D: Micronized dehydrated human amnion chorion membrane injection in the treatment of knee osteoarthritis: A large retrospective case series. J Knee Surg 2021;34:841-845. [DOI] [PubMed] [Google Scholar]